title: Activated cyclin-dependent kinase 5 promotes microglial phagocytosis of fibrillar β-amyloid by up-regulating lipoprotein lipase expression.
abstract: Amyloid plaques are crucial for the pathogenesis of Alzheimer disease (AD). Phagocytosis of fibrillar β-amyloid (Aβ) by activated microglia is essential for Aβ clearance in Alzheimer disease. However, the mechanism underlying Aβ clearance in the microglia remains unclear. In this study, we performed stable isotope labeling of amino acids in cultured cells for quantitative proteomics analysis to determine the changes in protein expression in BV2 microglia treated with or without Aβ. Among 2742 proteins identified, six were significantly up-regulated and seven were down-regulated by Aβ treatment. Bioinformatic analysis revealed strong over-representation of membrane proteins, including lipoprotein lipase (LPL), among proteins regulated by the Aβ stimulus. We verified that LPL expression increased at both mRNA and protein levels in response to Aβ treatment in BV2 microglia and primary microglial cells. Silencing of LPL reduced microglial phagocytosis of Aβ, but did not affect degradation of internalized Aβ. Importantly, we found that enhanced cyclin-dependent kinase 5 (CDK5) activity by increasing p35-to-p25 conversion contributed to LPL up-regulation and promoted Aβ phagocytosis in microglia, whereas inhibition of CDK5 reduced LPL expression and Aβ internalization. Furthermore, Aβ plaques was increased with reducing p25 and LPL level in APP/PS1 mouse brains, suggesting that CDK5/p25 signaling plays a crucial role in microglial phagocytosis of Aβ. In summary, our findings reveal a potential role of the CDK5/p25-LPL signaling pathway in Aβ phagocytosis by microglia and provide a new insight into the molecular pathogenesis of Alzheimer disease.
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Yuanhui
authors.initials: Y
authors.lastname: Ma
authors.forename: Jintao
authors.initials: J
authors.lastname: Bao
authors.forename: Xuyang
authors.initials: X
authors.lastname: Zhao
authors.forename: Hongyan
authors.initials: H
authors.lastname: Shen
authors.forename: Junniao
authors.initials: J
authors.lastname: Lv
authors.forename: Shuaipeng
authors.initials: S
authors.lastname: Ma
authors.forename: Xuefei
authors.initials: X
authors.lastname: Zhang
authors.forename: Zeyang
authors.initials: Z
authors.lastname: Li
authors.forename: Shuxin
authors.initials: S
authors.lastname: Wang
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Wang
authors.forename: Jianguo
authors.initials: J
authors.lastname: Ji
mesh_terms: D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D051360:Cyclin-Dependent Kinase 5; D008071:Lipoprotein Lipase